This application is a 371 of FCT/EP99/01023 filed Feb. 18, 1999.
The invention relates to a combination preparation of an oestrogen and an antioestrogen. Owing to the decreasing production of oestrogen, during the change of life and after the menopause acute symptoms needing treatment, such as hot flushes, suddenly occurring outbreaks of sweating, racing heart and other vasomotor symptoms occur in many women. The loss of the endogenous oestrogens can lead in the long term to an increased loss of bone mass (osteoporosis) and to an increase in cardiovascular disorders. More recent epidemiological investigations have shown that physiological and pathological ageing symptoms of the central nervous system are partially to be attributed to the loss of oestrogen. Examples of these which may be mentioned are limitations of the memory power of the short-term memory (S. M. Phillips, B. B. Sherwin, 1992, Psychoneuroendocrinology 17, 485) and Alzheimer""s disease (A. Paganini-Hill, V. W. Henderson, 1994, Am. J. Epidemiol. 140, 256).
Hormone replacement therapy has the aim of substituting the losses of the endogenous oestrogens commencing with the menopause and thus preventing both the acute and the long-term symptoms. Today the therapy is either carried out as oestrogen monotherapy or as combination therapy with gestagens. A disadvantage of the monotherapy is the proliferative action of the oestrogen on the endometrium, which can lead to endometrial hyperplasia and adenocarcinomas. With combination therapy, withdrawal bleeding or intracyclic menstrual bleeding occurs, which markedly restricts the acceptance of the therapy and frequently leads to the discontinuance of the therapy. Furthermore, adverse effects of the gestagens on the cardioprotective and positive central actions of the oestrogens are discussed.
A further possibility for hormone substitution is the combination of an oestrogen with an antioestrogen. In this case, the protective effects of the oestrogen in the bone should be retained, while the undesired effects on the endometrium should be antagonized (EP 0346014). It is, however, disadvantageous when the antioestrogen reaches the central nervous system and antagonizes the positive properties of oestrogen there. It is reported, for example, for tamoxifen that it induces typical, acute climacteric symptoms such as hot flushes (S. Litherland, M. Jackson, 1987, Cancer Treat Revs. 15, 183). It. was possible to show that the substance reaches the central nervous system and acts there as an oestroaenic antagonist (A. Biegon et al., 1996, Cancer Research 56, 4328). It would also not be desirable if the antioestrogen were to counteract the protective action of the oestrogen in Alzheimer""s disease.
The technical problem then lies in finding a combination preparation of an oestrogen and an antioestrogen in which the antioestrogenic component does not reach the central nervous system and simultaneously has an antiproliferative action on the endometrium.
The problem is now solved in that a combination preparation has been found in which the oestrogen is selected from the group consisting of 17-xcex2-oestradiol, 17-xcex1-ethynyloestradiol, oestriol, oestrone, oestrone sulphate, oestrogen sulphamates, 17xcex1-oestradiol, mestranol, stilboestrol, esters of 17xcex2-oestradiol, such as, for example, oestradiol valerate and naturally conjugated oestrogens and in that the antioestrogen is a substituted 7xcex1-("xgr"-aminoalkyl)oestratriene of the general formula I 
in which
the side chain SK is a radical of the subformula 
where m is 4, 5 or 6,
n is 0, 1 or 2,
x is 0, 1 or 2,
A is a hydrogen atom or a C1-5-alkyl group,
B and D are each a hydrogen atom, or
A and B together are an alkylene group xe2x80x94(CH2)pxe2x80x94 with p=2, 3, 4 or 5 and D is a hydrogen atom or
A and D together are an alkylene group xe2x80x94(CH2)qxe2x80x94 with q=2, 3 or 4 and B is a hydrogen atom, and
E is an unsubstituted or mono- to pentafluorinated ethyl radical, or the terminal substituent xe2x80x94(CH2)3xe2x80x94E in the side chain is replaced by an optionally substituted aryl or heteroaryl radical which is bonded to the sulphur atoms directly or via a mono-, di- or trimethylene group,
R3 is a hydrogen atom, a hydrocarbon radical having up to 8 carbon atoms or a radical of the subformula R3xe2x80x2xe2x80x94C(O)xe2x80x94, in which R is a hydrogen atom or a hydrocarbon radical having up to 8 carbon atoms or a phenyl radical,
R11 is a hydrogen atom, a halogen atom or a nitrooxy group xe2x80x94Oxe2x80x94NO2,
R14, R15xcex1, R15xcex2, R16xcex1 and R16xcex2 are each a hydrogen atom or
R14 and R15xcex1 are an additional bond or a methylene bridge, or
R15xcex2 is a methyl group and R15xcex1 is a hydrogen atom, or
R15xcex1 and R15xcex2 are each a methyl group, or
R15xcex2 and R16xcex2 together are a methylene bridge, or
R16xcex1 or R16xcex2 is a halogen atom or
R16xcex1 and R16xcex2 together are a methylidene group and the remaining substituents R14, R15xcex1, R15xcex2, R16xcex1 and
R16xcex2 are each a hydrogen atom,
R17xe2x80x2 in the xcex1- or xcex2-position is a hydrogen atom, a C1-5-alkyl, C2-5-alkenyl or C2-5-alkynyl group or a trifluoromethyl group and
R17xe2x80x3 is a hydrogen atom or a radical of the subformula R17xe2x80x2xe2x80x3xe2x80x94C(O)xe2x80x94, in which R17xe2x80x2xe2x80x3 is a hydrogen atom or a hydrocarbon radical having up to 8 carbon atoms, or, if R17xe2x80x2 is located in the xcex1-position, R17xe2x80x2 together with R14 is an ethano bridge,
with the proviso that, if A and B together are not xe2x80x94(CH2)pxe2x80x94 or A and D together are not xe2x80x94(CH2)qxe2x80x94, at least one of: the substituents R11, R14, R15xcex1, R15xcex2, R16xcex1 and R16xcex2 and R16xcex2 is not a hydrogen atom,
and their physiologically tolerable addition salts with organic and inorganic acids.
Moreover, a combination preparation is made available in which the oestrogen is selected from the group consisting of 17-xcex2-oestradiol, 17-xcex1-ethynyloestradiol, oestriol, oestrone, oestrone sulphate, oestrogen sulphamates, 17xcex1-oestradiol, mestranol, stilboestrol, esters of 17xcex2-oestradiol, such as, for example, oestradiol valerate and natural conjugated oestrogens and the antioestrogen is an 11xcex2-halo-7xcex1-substituted oestratriene of the general formula II 
in which
R3 is a hydrogen atom, a hydrocarbon radical having up to 8 carbon atoms or a radical of the subformula R3xe2x80x2xe2x80x94C(O)xe2x80x94, in which R3xe2x80x2 is a hydrogen atom or a hydrocarbon radical having up to 8 carbon atoms or a phenyl radical,
R7 is a radical of the formula xe2x80x94Axe2x80x94Bxe2x80x94Zxe2x80x94R20, in which
A is a direct bond or a benzylidene radical, where the methylene group is bonded to the 7-carbon atom of the steroid, or a phenylene radical,
B is a straight- or branched-chain alkylene, alkenylene or alkynylene group having 3 to 14 carbon atoms, and
Z is xe2x80x94NR21xe2x80x94 and R21 is a C1-C3-alkyl group, where R20 then is
a hydrogen atom,
a straight- or branched-chain alkyl, alkenyl or alkynyl group having up to 10 carbon atoms, or one of the groups
xe2x80x94Dxe2x80x94CnF2nxe2x88x921, where D is a straight- or branched-chain alkylene, alkenylene or alkynylene group having up to 8 carbon atoms and n is an integer from 1 to 8,
xe2x80x94Lxe2x80x94CHxe2x95x90CFxe2x80x94CpF2p+1, where L is a straight- or branched-chain alkylene, alkenylene or alkynylene group having 2 to 7 carbon atoms and p is an integer from 2 to 7,
xe2x80x94Dxe2x80x94Oxe2x80x94(CH2)q-aryl, where D has the meaning already indicated, q is 0, 1, 2 or 3 and aryl is an optionally mono- or disubstituted phenyl radical, 1- or 2-naphthyl radical or a heteroaryl radical,
xe2x80x94Dxe2x80x94Oxe2x80x94(CH2)rxe2x80x94CnF2n+1, where D and n have the meanings already indicated and r is an integer from 1 to 5, or
R20 and R21 with the nitrogen atom to which they are bonded form a saturated or unsaturated heterocycle having 5 or 6 chain members, which optionally contains one or two further heteroatoms selected from nitrogen, oxygen and sulphur, and is optionally substituted, or
Z is xe2x80x94SOxxe2x80x94 and x is 0, 1 or 2, where R20 then is
a straight- or branched-chain alkyl, alkenyl or alkynyl group having up to 10 carbon atoms, or one of the groups
xe2x80x94Dxe2x80x94CnF2n+1, where D is a straight- or branched-chain alkylene, alkenylene or alkynylene group having up to 8 carbon atoms and n is an integer from 1 to 8,
xe2x80x94Lxe2x80x94CHxe2x95x90CFxe2x80x94CpF2p+1, where L is a straight- or branched-chain alkylene, alkenylene or alkynylene group having 2 to 7 carbon atoms and p is an integer from 2 to 7,
xe2x80x94Dxe2x80x94Oxe2x80x94(CH2)q-aryl, where D has the meaning already indicated, q is 0, 1, 2 or 3 and aryl is an optionally mono- or disubstituted phenyl radical, 1- or 2-naphthyl radical or a heteroaryl radical,
xe2x80x94Dxe2x80x94Oxe2x80x94(CH2)rxe2x80x94CnF2n+1, where D and n have the meanings already indicated and r is an integer from 1 to 5, or
Z is xe2x80x94NR31xe2x80x94,
where R20 then is a straight- or branched-chain alkyl, alkenyl or alkynyl radical having up to 14 carbon atoms, which can be interrupted by one to three heteroatoms xe2x80x94Oxe2x80x94 and xe2x80x94Sxe2x80x94 and groups xe2x80x94NR32xe2x80x94, in which R32 is a hydrogen atom or a C1-C3-alkyl radical, and/or can be partially fluorinated, an optionally mono- or disubstituted aryl or heteroaryl radical, an optionally mono- or disubstituted C3-C10-cycloalkyl radical, an optionally mono- or disubstituted C4-C15-cycloalkylalkyl radical, an optionally mono- or disubstituted C7-C20-aralkyl radical, an optionally mono- or disubstituted heteroaryl-C1-C6-alkyl radical or an optionally substituted aminoalkyl radical, and
R31 is a radical of the formula xe2x80x94C(O)R33 or xe2x80x94CH2xe2x80x94R33,
where R33 then is a straight- or branched-chain alkyl, alkenyl or alkynyl radical having up to 14 carbon atoms, which can be interrupted by one to three heteroatoms xe2x80x94Oxe2x80x94 and xe2x80x94Sxe2x80x94 and groups xe2x80x94NR32xe2x80x94, in which R32 is a hydrogen atom or a C1-C3-alkyl radical, and/or can be partially fluorinated, an optionally mono- or disubstituted aryl or heteroaryl radical, an optionally mono- or disubstituted C3-C10-cycloalkyl radical, an optionally mono- or disubstituted C4-C15-cycloalkylalkyl radical, an optionally mono- or disubstituted C7-C20-aralkyl radical, an optionally mono- or disubstituted heteroaryl-C1-C6-alkyl radical, an optionally substituted aminoalkyl radical or a biphenylene radical,
excluding the compounds
11xcex2-fluoro-7xcex1-{5-[N-methyl-N-3-(4,4,5,5,5-pentafluoro-pentylthio)propylamino]pentyl}oestra-1,3,5(10-triene-3,17xcex2-diol
7xcex1-{5-[(2S)-2-(4,4,5,5,5-pentafluoropentylthiomethyl)-pyrrolidin-1-yl]pentyl}oestra-1,3,5(10)-triene-3,17xcex2-diol
7xcex1-{5-[(2R)-2-(4,4,5,5,5-pentafluoropentylthiomethyl)-pyrrolidin-1-yl]pentyl}oestra-1,3,5(10)-triene-3,17xcex2-diol
11xcex2-fluoro-7xcex1-{5-[2-(4,4,5,5,5-pentafluoropentylthio-ethyl)pyrrolidin-1-yl]pentyl}oestra-1,3,5(10)-triene-3,17xcex2-diol
11xcex2-fluoro-7xcex1-{5-[N-methyl-N-3-(4,4,5,5,5-pentafluoro-pentylthio)propylamino]pentyl}-3-hydroxyoestra-1,3,5(10)-trien-17-one
11xcex2-fluoro-7xcex1-{6-[N-methyl-N-3-(4,4,5,5,5-pentafluoro-pentylthio)propylamino]hexyl}oestra-1,3,5(10)-triene-3,17xcex2-diol
11xcex2-fluoro-7xcex1-{5-[(2S)-2-(4-trifluoromethylphenylthio-methyl)pyrrolidin-1-yl]pentyl}oestra-1,3,5(10)-triene-3,17xcex2-diol
11xcex2-fluoro-7xcex1-{5-[(2S)-2-(4,4,5,5,5-pentafluoropentyl-thiomethyl)pyrrolidin-1-yl]pentyl}oestra-1,3,5(10)-triene-3,17xcex2-diol
11xcex2-fluoro-7xcex1-{5-[(2S)-2-(4,4,5,5,5-pentafluoropentane-sulphinylmethyl)pyrrolidin-1-yl]pentyl}oestra-1,3,5(10)-triene-3,17xcex2-diol
11xcex2-fluoro-7xcex1-{5-[(2S)-2-(4,4,5,5,5-pentafluoropentane-sulphonylmethyl)pyrrolidin-1-yl]pentyl}oestra-1,3,5(10)-triene-3,17xcex2-diol
R11 is a fluorine or chlorine atom, R17 is a hydrogen atom or a radical of the subformula R17xe2x80x2xe2x80x94C(O)xe2x80x94, in which R17xe2x80x2 is a hydrogen atom or a hydrocarbon radical having up to 8 carbon atoms.
Combination preparation means that the oestrogen and the antioestrogen are made available in one pharmaceutical package in the same administration form or in different administration forms and are administered either simultaneously or successively. Antioestrogen means a substance which has no or only very low oestrogenic activity, binds to the oestrogen receptor and prevents the action of the oestrogen. An antioestrogen counteracts the increase in the uterus weight and/or the increase in the uterus epithelial depth in spayed female rats or mice which have been substituted with oestradiol benzoate. The sole treatment of spayed rats with the antioestrogen does not lead to the stimulation (increase) of the uterus weight or of the epithelial depth in comparison to untreated animals.
The compounds of the general formula I and II have a very strong antioestrogenic action and do not pass into the central nervous system. They are therefore particularly suitable for combining with an oestrogen, since they do not inhibit the positive properties of the oestrogen in the brain.
The ratio of the dose of the oestrogen to the dose of the antioestrogen is 1:5 to 1:100, preferably 1:20 to 1:200, most preferably 1:50 to 1:100.
The combination of an oestrogen with the antioestrogen 11xcex2-fluoro-7xcex1-{5-[N-methyl-N-3-(4,4,5,5,5-pentafluoro-pentylthio)propylamino]pentyl}oestra-1,3,5(10)-triene-3,17xcex2-diol is preferred.
The combination of an oestrogen with an antioestrogen which is selected from the group consisting of
11xcex2-fluoro-7xcex1-{5-[methyl-(8,8,9,9,9-pentafluoro-nonyl)amino]pentyl}oestra-1,3,5(10)-triene-3,17xcex2-diol 11xcex2-fluoro-7xcex1-{6-[methylxe2x80x94(8,8,9,9,9-pentafluoro-nonyl)aminolhexyl}oestra-1,3,5(10)-triene-3,17xcex2-diol
11xcex2-fluoro-7xcex1-{5-[methyl-(7,7,8,8,9,9,10,10,10-nonafluorodecyl)amino]pentyl}oestra-1,3,5(10)-triene-3,17xcex2-diol
11xcex2-fluoro-7xcex1-{5-[methylnonylamino]pentyl}oestra-1,3,5(10)-triene-3,17xcex2-diol
11xcex2-fluoro-7xcex1-{5-[3,4,4,5,5,5-hexafluoropent-2-enyl)methylamino]pentyl}oestra-1,3,5(10)-triene-3,17xcex2-diol
11xcex2-fluoro-7xcex1-{5-[N-methyl-N-3-(4,4,5,5,5-penta-fluoropentyloxy)propylamino]pentyl}oestra-1,3,5(10)-triene-3,17xcex2-diol
4-biphenyl-N-[6-(11xcex2-fluoro-3,17xcex2-dihydroxyoestra-1,3,5(10)-trien-7xcex1-yl)hexyl]-N-(3-phenylpropyl)-acetamide
is additionally preferred.
The antioestrogen can be administered orally, transdermally, as an implant or intravenously. The oestrogen can be administered orally, transdermally, intravenously or as an implant. All possible combinations of the administration forms for oestrogen and antioestrogen are possible here.
The invention furthermore relates to the use of the combination preparation according to the invention for the production of a medicament for male and female hormone substitution therapy. This can be used for the prevention and therapy of post-menopausal osteoporosis, in the case of climacteric symptoms and in Alzheimer""s disease. Further indications are the therapy of hot flushes, of depressive conditions due to the change of life, improvement in cognition, cardiovascular protection and therapy, immunoprotection, the therapy of symptoms as a result of dysmenorrhoea, of dysfunctional uterine haemorrhages, acne, restenosis, hypercholesterolaemia and of hyperlipidaemia, the prevention and treatment of arteriosclerosis, the prevention of loss of bone mass in women who have had a hysterectomy or in women who have been treated with LHRH agonists or antagonists, the treatment of endometriosis and myomas in combination with LHRH analogues and the inhibition of the proliferation of the arterial smooth muscle cells.
The invention further relates to pharmaceutical agents or compositions which contain the combination preparation according to the invention, if appropriate together with the formulating substances and additives customary in pharmacy.